Rare HIV-1 infected individuals display a significant level of broadly neutralizing antibodies that reflect a pattern of neutralization (i.e. breadth) and potency (i.e. relatively high titer). We hypothesize that the definition of the neutralization specificities present in broadly neutralizing patient sera will tell us the best targets upon which to focus immunogen design efforts to elicit broadly neutralizing responses. Because the regions of Env that are the targets for sera displaying breadth are not yet fully defined, this is important information to guide immunogen design. Such sera demonstrate that given the proper immunogenic stimulus, it is possible to elicit broadly neutralizing HIV antibodies. Using a multi-pronged approach we are identifying the neutralization specificity in the sera by a combination of selective protein-peptide adsorptions, chimeric viruses and by the direct isolation of novel B cell clones. In parallel, we continue to analyze candidate Env-based immunogens in small animals and are mapping the specificity of the elicited neutralizing activity.